Dopa, structure

M. Brunner-Guenat, P. A. Carrupt, G. Lisa, B. Testa, S. Rose, K. Thomas, P. Jenner, P. Ventura, Esters of L-Dopa Structure-Hydrolysis Relationships and Ability to Induce Circling Behaviour in an Experimental Model of Hemiparkinsonism , J. Pharm. Pharmacol. 1995, 47, 861 -869. 

Dopa — see Phenylalanine, dihydroxy-Dopplerite structure, 6, 849 Douglasite structure, 6, 846 Down s syndrome Alzheimer s disease, 6,770 DPP A process, 6,911 Drugs absorption metals, 6, 774... 

Colorimetric procedures used In steroid assays are often subject to drug Interference. In the determination of 17-Ketosterolds by the Zimmerman reaction, drugs with the 17-Keto basic structure such as ascorbic acid, morphine and reserplne will cause Increased values. In the determination of 17,21 -dlhydroxysterolds by the Porter-Sllber reaction the dlhydroxy-acetone chain Is the reactive unit. Drugs like meprobamate, chloral hydrate, chloropromazlne and potassium Iodide will Interfere with this reaction and cause elevated values. In the colorimetric determination of vanlllylmandellc acid (VMA) by a dlazo reaction, drugs like methocarbamol and methyl dopa cause... 

Blocking the conversion to DA would appear stupid unless this could be restricted to the periphery. More dopa would then be preserved for entry into the brain, where it could be decarboxylated to DA as usual. Drugs like carbidopa and benserazide do precisely that and are used successfully with levodopa. They are known as extracerebral dopa decarboxylase inhibitors (ExCDDIs). Carbidopa (a-methyldopa hydrazine) is structurally similar to dopa but its hydrazine group (NHNH2) reduces lipid solubility and CNS penetration (Fig. 15.4). 

Allomelanins — These are structurally different compounds containing little or no nitrogen. They are considered polymers of phenolic compounds like catechol. Fnngi prodnce melanin pigments, predominantly dihydroxyphenylalanine (DOPA)-melanin and dihydroxynaphthalene (DHN)-melanin. ... 

Furthermore, the presence of CB1 in the structures and pathways associated with the pathophysiology of Tourette s syndrome, and especially the functional link between CB1 and Di, D2, also argues that the endocannabinoid system may have some involvement in this disorder as well (Consroe, 1998). In addition, it has been suggested that activation of CB1 receptors, also owing to their link with the dopaminergic system, may reduce dyskinesia produced by L-DOPA in patients with Parkinson s disease (Brotsie, 1998). 

DOPA decarboxylase, should permit more efficient utilization of DOPA. A compound very closely related structurally to the substrate for the enzyme fulfills this function. Carbidopa 168 was designed for this purpose. Carbidopa s synthesis begins with a modified Strecker reaction using hydrazine and potassium cyanide on arylacetone 165 to give 166. This is then hydrolyzed with cold HC1 to give carboxamide 167. 

A variety of alkyl amines B, including 1-propylamine, ethylene diamine, 1,3-diaminopropane, and (7 )-l-amino-2-propanol have been used as reactants. The guest exchange kinetic results are reported in Table 13. The presence of more than one reacting [/3-CD-H-A] structure is observed with A = DOPA and penicillamine. The results have been rationalized in terms of specific interactions in the relevant inclusion complexes which determine their structure and relative stability. 

The molecular asymmetry of 9 is due to the four axial pendants containing the chiral L-vahne group. The efficiency of the gas-phase exchange reaction 30 where A are representative amino acids and B is either (5)-(- -)- or R)- — )-2-butylamine is appreciably affected by the configuration of both A and B. The guest exchange kinetic results are reported in Table 17. The presence of more than one reacting [9-H-A]" structure is observed with A = DOPA. A similar behavior was observed with permethylated /8-CD as the host." " ... 

For aromatic amino and hydrazino acids and several other structurally related compounds, the influence of MeOH content in both RP and POM was investigated on a teicoplanin CSP [90]. Using a hydroorganic mobile phase, complete enantiosep-arations of a-methylamino acids were not attained. However, this type of separation was suitable for the enantiomers of dopa. Further experiments performed by the same authors in POM allowed the complete enantioseparation of a-methyl-ooPA enantiomers [91]. 

Carbidopa therefore inhibits the conversion of L-dopa to dopamine in the peripheral tissues and the blood while leaving it unchanged in the brain. The combination of L-dopa and carbidopa is marketed as Sinemet and was the treatment of choice for parkinsonism for many years. Note the structural similarity between carbidopa and L-dopa. Carbidopa looks enough like L-dopa to occupy the L-dopa site on the decarboxylase. At the same time, the subtle structural differences render carbidopa indifferent to the enzyme. It is an inhibitor, not a substrate. 

An alternative delivery strategy for small molecules is based on the presence of the nutrient transporters. Drugs that are structurally similar to substrates of a carrier system can undergo facilitated brain uptake as pseudoneutrients. The best example of this is the therapeutic use of L-DOPA in Parkinson s disease. Unlike the neurotransmitter dopamine itself, which cannot cross the BBB in significant amounts, its precursor L-DOPA is a substrate for LAT, the transporter of large neutral amino acids [56]. Its uptake by the brain is saturable, and subject to competition by the other substrates of the carrier present in plasma. 

The noradrenaline normally contained in the storage granules can be partly or completely replaced by structurally related sympathomimetic amines, either by injection of the amine itself, or of suitable precursors such as a-methyl-DOPA or a-methyl-w-tyrosine. These amines can be depleted from the heart by guanethidine in the same way as the noradrenaline which they had replaced. a-Methylnoradrenaline [337] and metaraminol [338] are depleted less readily than noradrenaline from rabbit or rat hearts, whereas dopamine, octopamine and w-octopamine are depleted more readily than noradrenaline [339]. The more rapid depletion of these last three compounds was attributed to weaker binding in the storage granules [339], but could equally well be due to their greater susceptibility to destruction by monoamine oxidase, since both a-methyl-noradrenaline and metaraminol are resistant to attack by monoamine oxidase. 

Vitamin C is essential for the formation of collagen, the principal structural protein in skin, bone, tendons, and ligaments, being a cofactor in the hydroxylation of the amino acids proline to 4-hydroxyproline, and of lysine to 5-hydroxylysine. These hydroxyamino acids account for up to 25% of the collagen structure. Vitamin C is also associated with some other hydroxylation reactions, e.g. the hydroxylation of tyrosine to dopa (dihydroxyphenylalanine) in the pathway to catecholamines (see Box 15.3). Deficiency leads to scurvy, a condition characterized by muscular pain, skin lesions, fragile blood vessels, bleeding gums, and tooth loss. Vitamin C also has valuable antioxidant properties (see Box 9.2), and these are exploited commercially in the food industries. 

The physical and chemical behavior of molecules is largely determined by their constitution (the type and number of the atoms they contain and their bonding). Structural formulas can therefore be used to predict not only the chemical reactivity of a molecule, but also its size and shape, and to some extent its conformation (the spatial arrangement of the atoms). Some data providing the basis for such predictions are summarized here and on the facing page. In addition, L-dihy-droxyphenylalanine (L-dopa see p.352), is used as an example to show the way in which molecules are illustrated in this book. 

A number of 2,3-methanophenylalanine derivatives are efficient inhibitors of DOPA carboxylase [64]. For instance, 2-(3,4-dihydroxyphenyl) ACC 57, due to its structural analogy with a-methyl DOPA 58, is a reversible time-dependent inhibitor of DOPA carboxylase and of tyrosine amino transferase, Eq. (22) [65]. 

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